Key points

Adherence
to treatment and retention in care are important challenges for all HIV
treatment programmes, especially where resources are limited.

Retention
in care after one year in many treatment
programmes in sub-Saharan Africa is 60%,
indicating that a lot of patients are being lost and a lot of time and
money is being wasted preparing patients for treatment and treating them
for a few months. Much less time and money is being invested in finding these patients once they fail to return to the clinic.

More attention need to be given to finding
the patients who don’t return to the clinic, and finding the most
cost-effective methods for doing so.

At present
defining a gold standard for adherence measurement tools is difficult; there are many tools and each has its
advantages and disadvantages.

Clinics
that can dedicate more staff time to tracing defaulters, and going out
into the community to do so, may have lower rates of loss to follow-up.

The
longer that a clinic leaves it to follow up a missing patient, the more
likely they are to be permanently lost to follow-up.

Retention
of patients not yet on ART is important; patients lost to follow up before
they are eligible for treatment could become late presenters who only turn
up when seriously ill.

Offering
cotrimoxazole prophylaxis may improve retention in care for those not
yet eligible for ART.

ART
preparedness counselling requirements may be onerous, and further work is
needed to examine whether they are responsible for the disappearance of
patients.

Fast-tracking of patients of patients at high risk of serious
AIDS-related illness should be a priority.

Among
those already on treatment, younger adults may need special attention to
prevent loss to follow-up.

Support
groups and pill counts were associated with better adherence in a Nigerian
study, but it may be the feeling of accountability of the patient to the
health care worker, rather than the monitoring effect of spotting missed
doses, that makes pill counting more effective.

Ensuring good adherence and retention in care continue
to be two of the biggest challenges facing antiretroviral treatment programmes
as they scale up. Good adherence to medication, to clinic visits and to
pharmacy visits are all critical in ensuring the best possible outcomes for
patients.

Adherence and retention are also critical issues for
treatment programmes from a cost-effectiveness point of view. As programmes
seek to maximise the impact of limited resources, it is becoming apparent that
failures in ensuring good adherence and lack of attention to loss-to-follow-up
are costly.

Patients who do not adhere to treatment are more
likely to develop drug resistance and require more expensive second-line
treatment, or will fall ill as a result of treatment failure and require
hospital care. Patients lost to follow-up will require tracing, and may
reappear as hospital cases due to the interruption of their treatment.

Patients who disappear from care prior to starting ART
may also turn up later, in need of hospital care, or may simply die before
reaching the clinic again.

All of these outcomes place further stress on an
over-burdened health system, as well as representing individual human suffering
that ought to be preventable.

However, working out how to prevent these losses in
the most effective and cost-effective way is a challenge for treatment programmes, and at
last month’s Conference on Retroviruses and Opportunistic Infections
specialists from treatment programmes in sub-Saharan Africa
reported on research designed to identify which measures might be most
successful in ensuring good adherence and limiting loss to follow-up.

Insights from a themed discussion at CROI

“To be
successful on ART, the patient needs to accept it, be adherent — and also needs
to be retained in care,” said Dr Jean Nachega, who is with both Johns Hopkins and Stellenbosch University.1 “Our group has been able to show that we need to invest in
learning how to monitor adherence and to improve adherence, because at the end
of the day you are going to be saving money for the taxpayer. People who are
poorly adherent cost a lot because of the high hospitalisation rate.”

Dr Nachega was
speaking as a co-moderator of a themed discussion on retention and adherence to
care at this year’s Conference on Retroviruses and Opportunistic Infections
held in Boston,
from February 27 - March 2, 2011. Dr Nachega gave an overview on this topic before introducing eight researchers who
gave short descriptions of their recent work in the field, with a panel
discussion moderated by Dr Wafaa El Sadr, of Columbia
University and director of the International Center for AIDS Care and Treatment
Programs (ICAP). While not a comprehensive review, the session did offer some
useful insights, and can be viewed as a webcast here.

A brief overview of adherence interventions

The evidence of the high cost efficiency for good
adherence to which Dr Nachega was referring came from a recent cohort study
with over 6800 patients conducted in South Africa. The study found that
although some costs, such as those of medication, were higher in people with
excellent adherence, they were more than offset by dramatically reduced
hospitalisation costs as a result of maximally effective treatment of their HIV
disease.2 The same could hold true
for many interventions to improve adherence and retention in care — which appear
to cost more upfront, but may wind up saving money in the end.

This has been demonstrated for the majority of adherence
monitoring interventions, but as Dr Nachega illustrated with the following
table, there is no gold standard tool to monitor adherence.

“They all have their advantages and disadvantages,” he
said, but he highlighted a couple. One involved a study his group also
performed that was able to show that monitoring pharmacy refill closely can be
better than CD4 monitoring for detecting breakthrough viraemia.3

He believes another major advance in the field may be
real time monitoring tools.4 Some of these tools
combine cell phone technology with an electronic pill box, which alerts a
centralised web server whenever the pill box is opened. If the patient forgets
to take their medication, the web server sends their cell phones a text
message. A number of these systems have been piloted recently, such as the Wisepill dispenser
system in a small study in Uganda or the Med-eMonitor System.5 6 If scaleable, “and if we assume the cost is going to be going down, we’ll be
able to make a really major advance,” Dr Nachega said.

If anything, though, data seem to suggest that
adherence to ART in resource-limited settings is comparable if not better than
in North America.7 Even so, challenges remain,
including routine problems caused by alcohol or substance use, depression, side
effects, pill burden/dosing frequency, memory, or adolescence. In addition,
structural challenges need to be addressed such as the costs for the
patient associated with transportation to the clinic, food insecurity,
stock-out and substitutions and of course, stigma.

In terms of
interventions to improve adherence, Dr Nachega highlighted two approaches. One,
directly observed therapy (DOT) for ART, he said doesn’t appear to work well in
the general population, according to a recent systematic review based on high
quality evidence from randomised controlled
trials, though the approach still might be useful in special populations.8

“But the most
exciting data are on using cellphones in resource-limited settings. These cell
phones are so popular, even grandma has her cellphone! We now have randomised
controlled trials highlighting that this kind of approach may be of use, so we
need now to think of how to implement it widely,” Dr Nachega said.9 10

The other major
issue addressed by the session was how to retain
people under care, as highlighted by a systematic review by Rosen et al which
found that by two years retention in most of the African programmes is only
around 60%.11
Loss to follow-up was the most common cause of attrition, followed by death.

Dr Nachega
pointed out that one of the speakers in the session, Dr Elvin Geng (see below)
had published work on the importance of accurately assessing survival among the
losses to follow-up — since failure to do so may make it difficult to
accurately identify modifiable risk factors for mortality in ART programmes.
Without accurate information the programme’s response could fail. While tracking
all the losses to follow-up could be difficult, the paper suggests that a
sampling-based approach to account for losses to follow-up could be a feasible
and potentially scaleable method of tracking and ascertaining causes of loss to
follow-up.12

As for strategies to improve retention in care, Dr
Nachega cited a recent paper from Professor Anthony Harries.13

“We need to try to set up and maintain simple
standardised monitoring systems,” said Dr Nachega. These should track number of
patients starting ART (every month or quarter) and avoid an overload of data. “We need to reduce indirect patient costs -
all the structural barriers like transport to the clinic, perhaps through
providing reimbursement for transport, or by delivering home-based care as in
the trial from Jinja, Uganda,” he said.14

“Obviously, we need to try to prevent drug
interruptions,” he said. Prof Harries’ paper stressed lessons learned from TB
programmes, to ensure uninterrupted drug supplies by activating drug
forecasting, securing drugs supplies and prioritising a few standardised
regimens. In the case of ART, the regimens should be as simple and non-toxic as
possible so that they are easy to administer, and can be given by paramedical
staff. Treatment should of course be freely provided.

“Most importantly we need to decentralise ART clinics
and reduce the frequency of visits,” said Dr Nachega. In other words, ART care
needs to move beyond specialised facilities to rural hospitals and health
centres, with patient management tasks shifted to nurses and paramedical staff
as much as possible.

Before introducing the session speakers, Dr Nachega
stressed that the greatest threat to the retention in care of people living
with HIV may be the international financial crisis.

“Some donors are stopping funding programmes in Africa, so that patients who are eligible are not likely
to get started on ART,” he said. “We need to continue our advocacy to make
certain that major donors, including PEPFAR, maintain their funding.”

After Dr Nachega spoke, a number of speakers followed.
Notably, not all of their findings were consistent with each other or with
published data. However, as Dr El Sadr noted, each programme can have its
own approach to monitoring or to an intervention — and going forward, it will
be important to characterise the activities in order to identify elements
leading to their success or failure.

Not all the 'lost to follow-up' are lost

“Loss to follow-up is common among ART programmes but
it’s not consistently defined,” said Dr Aima Ahonkhai of Massachusetts
General Hospital in Boston, who presented the
findings of a large retrospective cohort study of adults initiating ART in the
South African Catholics Bishops Conference and Catholic Relief Services HIV
Treatment Programme between 2004 and 2008.15

The study’s objectives were to assess outcomes among
different sub-groups often defined as lost to follow-up; to determine risk
factors associated with these outcomes; and to evaluate trends in these
outcomes over time. The analysis included 11,397 patients, with a median
follow-up of 2.4 years. At study
conclusion, 63% remained in care — however, not all were
entirely lost to follow-up. Some clearly were, for instance, 9% of patients had died in the first seven months on ART, while 17% were lost to follow-up and
missed all routine follow-up appointments in the first year on ART. But the
remaining 11% of patients had only interrupted care. They missed all of their
appointments in the first seven months on ART but returned to clinic before the year
was over and resumed treatment.

“Patients with interrupted care had excellent clinical
outcomes, upon return to clinic the median CD4 count increased to 257 cells and
84 percent had a viral load of less than 400 copies,” she said. On the other
hand, patients who suffered early deaths, were the most ill at baseline, with a
median CD4 count of 48 cells.

Compared to patients who remained in care, male sex
predicted all other outcomes, but no other baseline risk factors or patient
factors predicted, or differentiated between, interrupted care and loss to
follow-up.

In contrast to some other expanding programmes, Dr
Ahonkhai said that losses to follow-up have decreased over time. But she
concluded that “because baseline risk factors do not distinguish interrupted
care from lost to follow-up, more resources are needed for health information
systems.”

Programme characteristics that impact retention in care

Factors such as having dedicated staff and vehicles to
follow-up on patients, as well as the time interval to tracking down the
patient may have a dramatic impact on retention in HIV care, according to
analysis of programmatic data presented by Dr Paula Braitstein, of Indiana
University School of Medicine and the USAID-AMPATH partnership in Eldoret, Kenya.16

The analysis was based upon data from IeDEA, the
International Epidemiologic Databases to evaluate AIDS, a multi-regional
consortium including 29 ART clinics around East Africa - Uganda, Tanzania
and Kenya. The programme level data for the analysis was
drawn from two rounds of site assessments in 2007 and then by clinic
self-report in 2009. Included in this analysis were all individuals aged at
least 18 years and on ART at their last visit.

The primary outcome was lost to follow-up, defined as
being absent from the clinic for at least 6 months. The Weibull survival model
was used to model the time to lost to follow-up. A separate model was used for
each of the outreach variables of interest: “basically,” she said, “who does
the outreaching; how do they do it; and when do they do it?” A random effect
was included in the model to account for correlation among patients from the
same site; and the model adjusted for patient age, sex, CD4 count at ART
initiation and WHO stage at ART initiation.

The analysis involved 43,175 patients, 61 percent
female; with a mean age of 38.4 years.
The incidence of lost to follow-up was 16.5 per 100 person years to
follow-up, but varied tremendously from site to site (from 1 to 79.5 per 100
person years).

The analysis looked at three programmatic
characteristics, which Dr Braitstein said “brought it down to the lowest common
denominators so that there was enough homogeneity within the groups to do the
analysis properly.”

1) Did the clinic
have dedicated staff for follow-up, or did they either not have dedicated staff
or only use the telephone for follow-up (clinics with the latter two
characteristics were more or less similar)? Using only the telephone or having
no dedicated staff at all was associated with greater than 3-fold increased
risk of patients lost to follow-up (adjusted hazard ratio 3.36, 95% confidence
interval 1.72, 6.57) compared to clinics who had dedicated staff to do their
outreach (p=0.001).

2) Did they only
use public means, bicycle or walk to conduct follow-up, or did they also have
access to a vehicle for follow-up? Compared to clinics who used all available
means to go outreaching - which includes the use of a private vehicle - clinics
that only use public means, bicycle or foot-power had a three-fold increase in
the risk of patients lost to follow-up (3.12 adjusted hazard ratio, (95% CI
1.41, 6.88) p=0.009).

3) “And compared
to going looking for patients within 30 days, clinics that wait more
than 30 days to go looking for a patient were much more likely to have patients lost to
follow-up,” Dr Braitstein said, (aHR 2.32 (95% CI 1.26, 4.24), p=0.011)

“There’s a lot of heterogeneity between all the
different clinics as to what they do,” she said. “So for example at AMPATH in Western Kenya where I work, there’s a whole algorithm: If you are newly started on ART and you miss
a visit, somebody tries to find you within 24 hours. If you’re stable on ARVs they wait a
week. If you’re a child on ARVs, it’s 24
hours. Some clinics wait until people are lost to follow-up [> 6 months],
before they actually go and look for them.”

However, Dr David
Moore from Vancouver
pointed out that all the programme
characteristics that would seem to make a difference cost more money.

“So it would seem that there would be a general trend
that better funded programmes actually perform better. So is it possible to actually tease out these
specific characteristics of better funded programmes, from the overall effect
of better funding for individual programmes?” he asked.

Dr Braitstein conceded that this question needs more
examination, but went on: “Although some things are more costly, relative
to the cost of losing all of these patients who you’ve already invested so much
in, maybe it’s worthwhile to pay community health workers or peer outreach workers,
thinking in terms of priorities and how to balance”.

She
suggested that programmes need to look at the cost-effectiveness of providing
cotrimoxazole prophylaxis or food aid in the context of the programme’s ability
to retain people in care.

Retention of patients not yet on ART

Are ART preparedness requirements leading to high loss
to follow-up among people who qualify for ART but have not yet started?

Patients with CD4 counts of less than 250 require
timely initiation of ART but structural, behavioural and psychosocial barriers
may pose barriers to ART initiation. Losses to follow-up (i.e., unknown
outcomes) at this stage are high and prevent complete observation of patients’
outcomes, according to Dr Elvin Geng of the University
of California, San Francisco.17 As already noted, Dr Geng has published on the use of
sampling to try to ascertain what is going on with patients who are lost to
follow-up, and has now expanded on his work with a study investigating the
causes of loss to follow-up among people who qualify for ART but for one reason
or another, do not start.

“We used a sampling-based approach which fills in
outcomes through tracking a random sample of lost patients to evaluate ART
initiation at a proto-typical, high-volume, semi-rural scale-up clinic in
south-western Uganda and where two to three counselling sessions and a
treatment supporter are typically required for ART initiation,” he said.

In the study, over a three-year period 2369 ART
eligible patients presented to the clinics. But by one year, 21% became lost
before ART initiation - defined as being at least 60 days late for a return
visit. In a random sample of lost patients, in which 82% of outcomes were ascertained,
the one year mortality was 31%.

After incorporating outcomes among lost patients into
the entire ART-eligible clinic population, Dr Geng and colleagues observed that
over the first 90 days, the fraction starting ART rises quickly. But then at
one year, only 69% of patients have initiated; 16% are waiting in care/for ART,
but continued to visit a clinic —mostly at a different clinic than the original
clinic; 7% are completely disengaged from care, meaning no visits to any clinic
at all; and 9% of patients have died before
ART initiation.

“The next question really is: why?” said Dr Geng. “The
requirements for adherence counselling are an important aspect of care and are
very widespread but perhaps their role in the time to ART initiation needs
further evaluation.”

“Make
no mistake, I think that counselling has a tremendous causal effect in how well
patients do after they start ART. But I
think we need to ask ourselves - do we need to evaluate what kind of selection
is going on at that point in time as well, and whether or not that selection
precludes a decent chunk of patients from initiating ART?”

The requirements of adherence counselling include the
need to make repeated clinic visits for counselling — which Dr Geng said in
their clinic’s protocol meant somewhere between two to four visits before being
initiated on ART — as well as the need to designate a treatment supporter (who
may also need to be trained). Other potential causes of failure to initiate
could include distance to clinic and time off work or family duties required to
make these visits.

“If these observations are true elsewhere, in the
roll-out to date, potentially over one million ART eligible patients who have
presented to care failed to initiate ART in a timely way. Strategies to engage ART eligible patients therefore
represent a public health priority,” he concluded.

Of particular concern are those patients who die
before they can be initiated onto treatment, some speakers noted during the
discussion section — so it may be best to fast track the most ill patients.

Dr Ahonkhai said that while
she agreed about the importance of the pre-ART preparation, education and
counselling, “I think in our cohort we found that the median time to ART
initiation was 30 days in a very large multisite programme in South Africa —
and the South Africa National Guidelines now recommend fast tracking. Fast
tracking, particularly of patients who present with the most advanced disease,
is another important programmatic uptake that can be [implemented].”

Dr El Sadr said that awareness needed to be raised among clinic staff about the urgency of getting this group of patients onto treatment, “Maybe by setting up
something like a clock [or a timer]. The clock starts ticking from when the
person is identified to be eligible so that there’s an awareness that the clock
is ticking [among] the clinic staff and they’re trying to meet the deadline,” she suggested.

“People
can delay because they cannot afford travelling to facilities where ART can be
found," said Dr Geng. “Lastly we need to
remove stigma - to fight stigma - to actually ensure that stigma is not there
because it contributes a lot to preventing people from accessing ART. They
don’t want to come forward for fear of being known by the community that they
are HIV-positive.”

Could providing preventive therapy retain people with
HIV not yet on ART in care?

“I
think all of us are aware that most of the data on retention and adherence have
really focused on patients who have initiated ART. Until very recently the
group that was in care, or pre-ART, has not been given enough attention. So
that’s kind of a group that is important to highlight, to try to find
strategies to maintain these individuals in care so that they can initiate ART
in a timely manner,” said Dr El-Sadr.

One of
the basic concerns regarding retention of patients in care before starting ART
is creating incentives to remain engaged in care. After all, why should a
patient give up time and money and travel a long distance to the clinic if
there is no apparent health benefit and they feel well?

“Free
cotrimoxazole significantly improves retention amongst ART ineligible clients
in Kenya,” said Dr Pamela
Kohler of the University
of Washington, Seattle,
reporting on an analysis of data from a treatment programme in Nairobi.18 The aim of the study was to evaluate whether a
programme change — which was offering free cotrimoxazole prophylaxis to all
clients, regardless of CD4 count — was associated with improved retention in
care among ART-ineligible clients.

The analysis included 1024 ART-ineligible clients who
enrolled in the programme between 2005 and 2007. At that time, ART
ineligibility was defined as having a CD4 count greater than 250, and WHO stage
one or two disease. One-year retention in care among those enrolled was
compared before (n=610) and after (n=414) free cotrimoxazole prophylaxis was
offered. There were no significant differences in age, gender, TB status, BMI
or CD4 count associated with time of access to care. However those lost to
follow-up were significantly younger and had lower BMI than those who remained
in care.

The analysis found that those who enrolled after the
offer of free cotrimoxazole began had a significantly higher retention rate
(84% versus 63%), p<0.001, with a hazard ratio (adjusted for age, gender and
CD4 count)of 2.64 (95 percent CI
1.95-3.57, p<0.001).

In other words, those enrolled prior to implementation
of free cotrimoxazole were more than two and a half times more likely to be
lost to follow-up.

At the same time however, an analysis looking at
retention in the same time periods among those treated on ART found no
difference in the same time periods (89 and 88% retained in care) suggesting
that overall temporal programmatic changes were not responsible for the difference
seen in ART ineligible clients only.

“Although it’s not clear from these data, possible
mechanisms for this effect are decreased morbidity, perception of treatment,
lower cost of care or perhaps establishment of care-seeking habits,” said Dr
Kohler. “The implications of this analysis is that today’s ART ineligible lost
to follow-up are quite possibly tomorrow’s late presenters, and that losing
these clients presents missed opportunities for timely initiation of ART and
for messaging [to promote positive health dignity and prevention].”

This approach might work for other preventive care
measures, such as isoniazid prophylaxis therapy to prevent TB (IPT), and more
generally, the effect of pre-ART prophylaxis on retention in care needs to be
evaluated in a variety of settings. Although uptake of cotrimoxazole is good in
some countries among patients already taking ART or those on TB therapy, it
continues to be an underused intervention among those ineligible for ART,
despite WHO recommendations.

More services may be needed to retain younger adults on ART in care

Significantly worse retention in
care was observed in younger adults on ART in Tanzania, according to a
retrospective study presented by Dr. Geoffrey Somi of that country’s National AIDS Control Programme.19

The study was conducted to assess the retention and
the clinical response among patients enrolled in the national ART programme,
through a clinic-based abstraction of six-monthly visit data. It utilised a retrospective cohort design
with multi-stage random sampling to come up with a nationally representative
sample out of 11 regions, 32 districts, 43 facilities, including a total of
2781 patients who were 15 years and above, and who started ART treatment between
2004 and August 2007.

Factors
associated with advanced HIV disease at baseline and attrition at 12 months

Advanced
HIV disease at baseline

AOR

95% CI

p-value

Under 30
years

1.63

1.35-1.97

<0.0001

Sex - Male

1.39

1.16-1.69

0.0004

Facility -
Rural

1.72

1.13-2.63

0.01

Attrition at
12 months

Under 30
years

1.64

1.25-2.17

0.0003

Sex - Male

1.7

1.32-2.18

<0.0001

Advanced
HIV disease at baseline

1.61

1.15-2.27

0.005

The study found there were good clinical outcomes for
those retained in care at 12 months in terms of CD4 gain, and weight gain. As
for retention in care, at 12 months 63% were alive on ART, 8% reported dead; 4%
were alive, ART status unknown, 25% attrition with an unknown cause. Retention
and clinical outcomes did not vary significantly by ART initiation date across
the study period.

However, retention was significantly worse in those
with baseline CD4 cell counts below 50, males and those below 30 years.

“We concluded that good retention and response was
maintained as client numbers rose by over 1600 percent, and the sites rose from
11 to 605. Young adults showed lower retention than older clients, and being a
young adult was associated with having advanced HIV disease at baseline,
suggesting that young adults are seeking care later,” said Dr Somi. “Causes of attrition
need to be identified and addressed - young adults appear to be a particular
area of concern.”

Adherence support

The value of
peer counsellors and nurse-based care for ART adherence promotion

A task-shifting approach using peer counsellors and
nurse based care may be just as effective at supporting adherence as standard
clinic models, according to Dr Flavia
Matovu, of the Mulago Hospital-Johns Hopkins Research Collaboration in Kampala, Uganda.20

“Based on the urgent need for lower cost programmes
aimed at achieving and maintaining higher levels of adherence to ART, we
conducted a randomised non-inferiority intervention trial to assess the
efficacy of peer counsellors and nurses in achieving/supporting adherence to
ART among Ugandan patients attending the PMTCT clinic at the country’s national
referral hospital,” she said.

Eighty-five participants were randomised to either of
two HIV intervention models: the standard clinic-based model or a task-shifting
intervention.

The standard clinic-based model promoted adherence
through routine counselling by a certified counsellor, with care provided by a
medical officer at each visit. This included shorter intervals between the
visits, and all participants were started on ART provided through the PEPFAR
programme by a hospital doctor.

The intervention model evaluated the effect of peer
counsellors, and the effect of home visiting combined with a greater emphasis
on nurses for routine visits, and also evaluated longer intervals between
clinic visits.

The primary outcome was virologic suppression below
400 copies/ml. Secondary outcomes
included a change in CD4 cell count, from baseline, change in weight and pill
adherence.

“A high level of adherence was maintained in both
models after adjusting for baseline viral load,” said Dr Matovu. The task-shifting
had similar outcomes and was not categorically inferior to the standard model
that utilised doctors and counsellors. Essentially, there were no significant
differences in viral load, CD4 cell count, pill adherence, or changes in weight
over the 6 to 12 months follow-up period.

“These data are suggesting that ART adherence may be
effectively supported using nurses and peer counsellors for follow-up care
visits - a task shifting approach that may help deliver effective life-saving
treatment to many more HIV-infected people in resource-limited settings,” she
concluded.

Adherence better in women who have
started ART before pregnancy?

“Concerns have
been raised in the literature regarding the impact of pregnancy on adherence to
ongoing ART,” said Dr Rory Leisegang from the University of Cape Town, South
Africa. “Previous studies have shown that adherence decreases post-partum; and
that losses to follow-up for patients who’ve started ongoing ART while
pregnant, have increased.”

To better understand the impact of pregnancy on
adherence, a retrospective cohort analysis of women on ongoing ART in a South
African private sector managed-care ART programme was performed. The control
group included: 1) 4549 women on ART who were never pregnant, 2) 293 women who
started ART upon learning they were pregnant (prevalent pregnant) and (3) 128
who became pregnant after starting ART (incident pregnant).

There were two key outcomes: ART adherence, from
monthly refill data; and default on ongoing ART, defined as more than 6 months
default on monthly prescription refills.

“The women were enrolled in a private sector programme
and they received care through normal GPs. So they would have gone through the
same process as any other person would go through during a pregnancy — there
was no special care, no other special programme other than using the GPs with
hospital services in the area,” said Dr Leisegang.

The key findings from the study were that median
adherence was higher in the never pregnant, compared with the prevalent
pregnant group: 79 percent vs. 54 percent (p<0.001). Time to default was
indeed higher in people who started antiretrovirals while pregnant, with the
adjusted hazard ratio of 1.78 (95 percent CI 1.44 to 2.19). However, in the
never vs. incident pregnant groups, higher adherence (by logistic regression)
was associated with shorter time on ART (in other words, during the initial
stages of ART), and with older age — also in the incident patients, during pregnancy
and being 6 months post-partum.21

One member of the
audience asked whether there was any variation during pregnancy — whether
perhaps nausea and vomiting during the first
trimester might be associated with worse adherence, but the study has not yet
been able to show such effects. But another quandary was why adherence improved
in incident pregnancy but not prevalent pregnancies.

“I
think you have to think of them as two different groups. Women get screened
when they are pregnant, and often they are starting antiretroviral therapy
because someone has told them to start antiretroviral therapy [immediately],”
said Dr. Leisegang.

“We
won’t necessarily get people with higher CD4 counts onto programmes unless we
can improve why people don’t take their antiretroviral therapy in cases where
they may be well, or where there may be added stresses,” Dr Leisegang concluded.

Which components are most effective in a package of adherence interventions?

“I work in a facility that provides care to about 6,000
HIV patients with a very comprehensive programme to retain patients in care —
both in the clinic, and as well as in the community component. But for us to be
able to sustain PEPFAR programmes, we have to be able to identify which are the
most efficient components of this programme,” said Dr Loice Achieng of AIC Kijabe Hosp, Kenya.22

In order to determine which specific elements of their
adherence programme contributed more to the success of ARV therapy, 301 HIV
patients on ARVs were prospectively observed for participation in adherence
activities within 6 months of initiating therapy. These included home visits by
community health workers, support groups in the community, pill counts
performed in front of the patient by clinicians, post-pharmacy counselling
after dispensing, and clinic visits. The primary endpoint was time to treatment
failure defined as death, lost to follow-up or with a detectable HIV-1 RNA at
one year as measured by Kaplan-Meier analysis.

Adherence was significantly different between those
patients who either: had the correct number of clinic visits; who were involved
in support groups; and who had pill counts performed by clinicians in front of
the patients.

Comparison of Adherence in Success and Failures by
Adherence Promoters

Factor

Days to Failure

Risk of Failure (Cox Model)

Success

Failure

Hazard Ratio

Home visits

463

394

0.98

Support groups

480

425

0.54

Pill counts

481

355

0.57

Post pharmacy counselling

461

338

0.61

Made clinic visits

503

391

0.46

“We found that support groups and pill counts are
associated with better adherence; clinic visits, and support groups and pill
counts performed by clinicians are associated with the best time to treatment
failure,” she said.

However, as some audience members pointed out, it is
important to find out whether these findings are really generalisable.

One asked whether having the clinician count out pills
is really practical when it comes to facilities with huge numbers of patients.

“Most
of the patients come in, they’ve probably missed a few pills. It probably just takes a minute or two to
actually count the pills with the patient in a clinic setting. And this is
probably the cheapest intervention of all,” Dr Achieng responded.
“Support groups involve a significant patient contribution, as well as being
able to ensure the support groups run. The other things we analysed like home
visits are quite expensive because you have to employ community health workers
to take part in the home visits. Pill counts seem to be the cheapest and easiest
to use in this setting.”

Why do
pill counts appear to work?

“I
think it’s a role of the clinician rather than any of the other providers,
because in the same study you’ll find that post-pharmacy counselling [is being
given] while the pharmacist’s at work,” said Dr Achieng. “Other studies have
shown that when patients were talked to by the clinician, as opposed to by
other members of the team, then they are more likely to adhere to treatment.”

In
contrast, “directly observed therapy is difficult to perform, for many
reasons: You have to have the patient,
the patient has to be there with you. So that may not work just because of the
logistics of having the patient there every day, several times a day.”

Dr Ahonkhai agreed that time with a clinician
counting the pills might improve adherence, but was less convinced about pill
counts themselves.

“Pill
count is neither sensitive nor specific but is going to depend on who’s doing
it, in which setting. Our experience about pill count overall has been very
poor, and especially when you deal with large programmes i.e. Global Fund,
PEPFAR with large numbers of people. So it’s not really perfect but [in fact]
far from it. So in terms of measurement,
there is intensive research to see how we can combine measurement which is simple
and practical to increase validity and reliability,” she said.

Another
audience member asked whether there might be early warning indicators of loss
to follow-up like pharmacy refill visit intervals?

“The
sector I work in is a managed care
sector and we have a database and I work on a team that is trying to use
multiple measures for tracking patients and then starting a phone call system
which can use either a CD4 count, a refill or doctor [as a prompt],” said Dr Leisegang. “[With the] databases - it’s
extremely useful that you have a pop-up system that comes on for counsellors
who then will phone patients and ask what’s going on. That’s often neglected because developing
countries don’t often have good databases.
But where there is, that’s what they do, they have a database
automatically kicking up and telling us that there are patients that are
missing their treatment.”

Other
panellists offered insights on potential early warning indicators in
other populations.

“We’re
working on an analysis right now in children, looking at the relationship of
missing visits and the risk of loss to follow-up. Because we think there’s
probably a strong relationship there," said Dr Braitstein. “And you might target more counselling around adherence
to clinic visits, for example, or try to find out what’s going on so that you
increase the retention of the children who are particularly a vulnerable group.
It’s also worth looking at some of the risk factors that have been identified
in the literature, like for example disclosure.
So if somebody’s never disclosed their HIV status, on some level it’s a
red flag that this patient is at high risk for becoming lost.”

“Or
men,” she continued. “We found that males were at a much higher risk of
becoming lost to follow-up, even after controlling for everything else. So we
probably need some specific interventions to try and address that. Maybe it’s
weekend and evening clinics?”

“From
our experience, in terms of patient preparation, the issues of disclosure that
have been brought up; the issue of having a treatment buddy, using the refill
history and clinic visit’s – have been very good pointers,” said Dr Matovu.“We
have a good community network of community health workers, some of whom are
actually patients, and these ones help us track the patients. One of the things
we do is have a very clearly defined catchment area. Previously we have had
programmes that had patients coming in from whichever place, and it’s very hard
to track these patients. When you have patients coming in from a well-defined
catchment area, we are able to reach them; we know where each patient lives, or
the community health worker in the area knows where each patient lives and you
are able to look for all of the patients.”

More research needed

Dr El
Sadr offered some final words to conclude the discussion

“There’s
tremendous interest and need for further research to try to really rigorously
evaluate the effectiveness of well described interventions — not every peer
programme is the same as the next peer programme; not every DOT programme is
the same/similar to the other one. If we can learn not just what works but why it works in terms of well-defined
programmatic characteristics and well-defined interventions; and then if we can
demonstrate their effectiveness, I think then we’ll be in a good position to
try to replicate them and scale them up.
So this is a very important area of research, and an important area of
further enquiry.”

[12] Geng
EH. Tracking a
sample of patients lost to follow-up has a major impact on understanding
determinants of survival in HIV-infected patients on antiretroviral therapy in Africa. Trop Med In Health 15 Suppl 1:63-9, 2010.

[15] Ahonkhai A et al. Not all
are lost: early death, care interruption, and loss to follow-up in a large South African community treatment programme. Eighteenth Conference
on Retroviruses and Opportunistic Infections, Boston,
abstract 1014, 2011. (Online here).

HATIP #176, April 12th, 2011

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

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This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends
checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member
of your healthcare team for advice tailored to your situation.